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Bleeding Disorders
Related synonyms: bleeding diathesis, clotting disorder, coagulation disorder, coagulopathy, haemostatic
disorder
Bleeding disorders are usually taken to mean coagulopathies with reduced clotting of the blood but also
encompass disorders characterised by abnormal platelet function or blood vessel walls that result in increased
bleeding. Bleeding disorders may result from faults at many different levels in the coagulation cascade. They can
range from severe and life-threatening conditions, such as haemophilia A, to much more mild variants. Some
bleeding symptoms (eg, bruising without obvious cause, nosebleeds and heavy menstrual bleeding) are quite
common in the general population and there is phenotypic variation even among individuals with defined bleeding
problems. Investigation of mild bleeding problems often fails to provide a diagnosis. [1]

The coagulation cascade [2]


When a blood vessel is injured, a series of biochemical reactions is brought into play. This has been presented in
the past as a coagulation 'cascade', describing a series of reactions necessary to achieve haemostasis by
developing a clot, stopping its formation at the right time,and eventually facilitating clot dissolution when the
vessel has healed. The scientific literature has moved towards the concept of a cell-based model which has
more relevance to in vitro mechanisms (see below). [3]
Nevertheless, the coagulation cascade is still useful in describing the sequence of events that occur in vitro.
Most of the proteins required for the cascade are produced by the liver as inactive precursors (zymogens) which
are then modified into clotting factors. There are two routes for activation of the coagulation system. The intrinsic
pathway is activated by contact with collagen from damaged blood vessels (or indeed any negatively charged
surface). The extrinsic pathway is activated by contact with tissue factor from the surface of extravascular cells.
Both routes end in a final common pathway - the proteolytic activation of thrombin and the cleaving of fibrinogen
to form a fibrin clot. The intrinsic pathway is the main 'player' in this scenario, with the extrinsic pathway acting as
an enhancer.

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The cell-based model


The original cascade proposed by McFarlane in 1964 has been developed over the ensuing decades. A newer
model describes the complex formed by tissue factor and factor VII. These participate in the activation of factor
IX, indicating that the intrinsic and extrinsic coagulation pathways are linked almost from the outset. [4] The new
cascade model identifies a role for endothelial cells and details the influence of host factors. [3]
Three stages are identified in the cell-based model in which it is envisaged that most of the processes involved
occur at the cell surface level: [5]
Initiation - tissue factor-expressing cells and microparticles are exposed to plasma.
Amplification - small amounts of thrombin induce platelet activation and aggregation and promote
activation of factors V, VIII and XI on platelet surfaces.
Propagation - this involves the formation of proteins (eg, tenase, prothrombinase) involved in the
formation of the thrombin clot.
Platelets are identified as having three functions - control of thrombin generation, support of fibrin formation and
regulation of fibrin clot retraction. Different populations of platelets with distinct surface properties are involved in
these coagulant functions. [6]

Classification
Congenital bleeding disorders
Haemophilia A (factor VIII deficiency) and haemophilia B (factor IX deficiency or Christmas' disease)
are the most well-known congenital bleeding disorders as well as celebrated examples of X-linked
genetic disease. [7] Other inherited bleeding disorders affecting the coagulation pathway are much
rarer and inherited in an autosomal recessive fashion; for example, prothrombin (factor II) deficiency is
found in about 1 in 2 million individuals.

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Von Willebrand's disease (vWD) is the most common inherited bleeding disorder. Usually the
condition is mild without spontaneous bleeding. It occurs equally in men and women and is caused by
reduced production or abnormality of Von Willebrand's factor (vWF) that both promotes normal platelet
function and stabilises factor VIII.
Rare autosomal recessive disorders (Glanzmann's thrombasthenia and Bernard-Soulier syndrome)
affecting platelet membrane glycoproteins and causing abnormal platelet binding and aggregation

Acquired disorders [8] [9]


Liver disease and cirrhosis cause reduced synthesis of clotting proteins and thrombocytopenia.
Vitamin K deficiency due to dietary deficiency, gastrointestinal malabsorption or absence of gut
bacteria in infancy (haemorrhagic disease of the newborn). [10]
Shock, sepsis or malignancy can all cause an increased bleeding tendency, often through the final
common pathway of disseminated intravascular coagulopathy (DIC) where simultaneous
microvascular thrombosis and generalised bleeding occur due to massive consumption of coagulation
factors or damage to vessel walls (for example, in meningococcal septicaemia).
Renal disease causes platelet dysfunction and reduced aggregation.
Circulating autoantibodies to coagulation factors (eg, in lymphoma and systemic lupus
erythematosus) or to platelets (as in immune thrombocytopenic purpura).
Amyloidosis where factor X deficiency occurs as well as local infiltration of blood vessels.
Vitamin C deficiency can cause diffuse haemorrhage in surgical patients. [11]
Advanced age can be associated with fragile veins. [12]
Prolonged steroid use is reputed to be associated with hypercoagulability and increased bleeding
tendency. However, one study found that this effect was likely to be of limited clinical
consequence. [13]
Remember that some diseases can be associated with both bleeding and thrombosis - eg, polycythaemia rubra
vera and essential thrombocythaemia. [14]

Presentation [15] [16] [17]


Symptoms
Bruising may be spontaneous or recurrent:
Large bruises on sun-exposed areas of limbs in the elderly are usually due to cumulative
ultraviolet vessel damage and are rarely significant. [18]
Large bruises on the trunk are more indicative of a bleeding disorder.
Prolonged bleeding:
After minor cuts or abrasions.
Nosebleeds lasting >10 minutes despite compression (especially in children).
Severe menorrhagia causing anaemia, with normal uterus.
Bleeding from gums without gingival disease and unrelated to brushing.
Following dental extraction.
Postpartum haemorrhage.
After injections or surgical procedures.
Also enquire regarding:
Current medication:
Including aspirin, non-steroidal anti-inflammatory drugs, warfarin and
complementary/alternative preparations.
Remember drug interactions between warfarin and other medications that prolong the
international normalised ratio (INR).
Family history of bleeding tendency.
Alcohol intake.
Other constitutional symptoms - eg, malaise, weight loss.
Past history or thrombosis (can be suggestive of thrombophilia).
Previous blood transfusions.
Renal or hepatic impairment.

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Signs
Systemically look for:
Pallor.
Sepsis.
Haemodynamic status.
Lymphadenopathy or hepatosplenomegaly.
Check:
Skin, palate and gums for:
Bruising
Petechia (non-blanching haemorrhagic spot <2 mm diameter)
Purpura (2-10 mm diameter)
Ecchymosis (>10 mm diameter)
Fundi for retinal haemorrhages.
Joints for haemarthrosis.
Rectal or vaginal examinations where appropriate.
Comparing coagulation factor and platelet defects [19] [20]
Coagulation factor defects

Platelet disorders and von Willebrand's


disease

Bruising on trunk and limbs

Large bruises

Small bruises

Bleeding from cuts

Relatively slight

Profuse

Nosebleeds

Uncommon

Common, frequently profuse and of long


duration

Gastrointestinal bleeding

Uncommon

Common

Haematuria

Common

Rare

Haemarthrosis

In severe haemophilia

Very rare

Bleeding after surgery or dental


extraction

Up to a day's delay before bleeding


occurs

Immediate bleeding

Investigations [1]
FBC, blood film and platelet count - may detect leukaemia, lymphoma or thrombocytopenia or
abnormal platelets.
Consider checking U&Es to exclude uraemia causing a platelet disorder.
Consider LFTs to detect hepatic cause of acquired coagulation factor deficiency and alcohol-related
damage.
Bone marrow biopsy.

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A coagulation screen usually involves taking blood in a mixture of citrate, EDTA and clotted sample
bottles. It includes:
Activated partial thromboplastin time (APTT):
This measures the intrinsic pathway (which includes factors I, II, V, VIII, IX, X, XI
and XII) and the common pathway.
A plasma sample is used and the intrinsic pathway is activated by adding
phospholipid, an activator such as kaolin (which acts as a negatively charged
surface) and calcium ions. The formation of prothrombinase complexes on the
surface of the phospholipid enables the formation of thrombin and a subsequent
clot. The result is reported as the time in seconds for this reaction.
The test is used to assess the overall competence of the coagulation system, as
a routine test to monitor heparin therapy and as a pre-operative screen for
bleeding tendencies. It will also reveal possible coagulation factor deficiencies,
as in haemophilia A and B.
Prothrombin time (PT):
This assesses the extrinsic and final common pathway of the coagulation
cascade, thus can detect factor I, II, V, VII or X deficiency or the effects of
warfarin.
It is performed by adding thromboplastin and calcium ions to a plasma sample.
The time for clot formation is measured.
Prolonged time suggests the presence of an inhibitor to, or a deficiency of, one
or more coagulation factors, the presence of warfarin, the existence of vitamin K
deficiency or liver dysfunction.
The INR, used to monitor warfarin, is derived by comparing the patient's clotting
time to that of a standardised sample.
Thrombin clotting time test:
This measures the rate of a patient's clot formation compared with a normal
plasma control. The plasma is first depleted of platelets and a standard amount
of thrombin added.
The test is used in the diagnosis of DIC and other conditions that can affect
fibrinogen level, such as liver disease.
If the above tests are all normal, the vast majority of common haemostatic disorders will have been
excluded. However, if symptoms persist and/or there is a suggestion of family history, patients should
be referred to a haematologist for further tests which may include:
Bleeding time - this tests the interaction between the platelets and the vessel walls. A
standardised spring-loaded lancet is used to make a small cut in the patient's forearm and
the time for the bleeding to stop is then measured. The test is not useful as a screening
test, as it has a high false positive result. It is sometimes used in the investigation of vWD
although even here it has poor specificity.
The platelet function analyser is a relatively new technique. It has largely replaced the in vivo
bleeding time test although it is not specific for, nor predictive of, any particular disorder and
its limitations need to be taken into account. [21] [22]
Fibrinogen - the level can be determined by immunological or functional assay. It is usually
performed when APTT or PT screening tests are prolonged. The main disorders detected
are afibrinogenaemia or hypofibrinogenaemia (due to absence or a low level of fibrinogen
production) and dysfibrinogenaemia (due to a molecular alteration of fibrinogen, causing
poor function). Differences in the level of fibrinogen measured by the two methods are
suggestive of dysfibrinogenaemia. [1]
Specific factor assays - factors VIII or IX to determine severity of haemophilia; factor VIII and
vWF in vWD.
Gene analysis looking for specific gene defects.

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Haemostasis tests in bleeding disorders [1] [23]
Platelet
count

Prothrombin
time

Activated partial
thromboplastin
time

Bleeding
time

Thrombin
time

Additional tests

Haemophilia A

Normal

Normal

Prolonged

Normal

Factor VIII low

Haemophilia B

Normal

Normal

Prolonged

Normal

Factor IX low

Von Willebrand's
disease

Normal

Normal

Prolonged or
normal

Prolonged

VWF and factor VIII


activity low and
impaired ristocetininduced platelet
aggregation

Liver disease

Low

Prolonged

Prolonged

Normal
(rarely
prolonged)

Disseminated
intravascular
coagulopathy

Low

Prolonged

Prolonged

Grossly
prolonged

Massive transfusion

Low

Prolonged

Prolonged

Normal

Oral anticoagulants

Normal

Grossly
prolonged

Prolonged

Normal

Heparin

Normal
(rarely
low)

Mildly
prolonged

Prolonged

Prolonged

Management
Management is dependent on the underlying condition - see separate articles on Haemophilia A (Factor VIII
Deficiency) and Haemophilia B (Factor IX Deficiency) and the separate article Von Willebrand's Disease.
Whilst the sex-linked nature of haemophilia results in mostly male sufferers, women are much more likely to
present with mild bleeding disorders due to the demands of menstruation and childbirth. Menorrhagia can be
tackled by standard means. For further details see the separate article on Menorrhagia.

Prevention
Those with serious inherited bleeding disorders may wish for genetic counselling and prenatal diagnosis. [24]

Further reading & references


The Haemophilia Society
Haemophilia guidelines; United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO)
Othman M, Chirinian Y, Brown C, et al; Functional characterization of a 13-bp deletion (c.-1522_-1510del13) in the
promoter of the von Willebrand factor gene in type 1 von Willebrand disease. Blood. 2010 Nov 4;116(18):3645-52. doi:
10.1182/blood-2009-12-261131. Epub 2010 Aug 9.
Guideline for the diagnosis and management of the rare coagulation disorders; AUnited Kingdom Haemophilia Centre
Doctors' Organization guideline on behalf of the British Committee for Standards in Haematology (Oct 2014)
1. Hayward CP; Diagnosis and management of mild bleeding disorders. HematologyAm Soc Hematol Educ Program.
2005:423-8.
2. Adams RL, Bird RJ; Review article: Coagulation cascade and therapeutics update: relevance to nephrology. Part 1:
Overview of coagulation, thrombophilias and history of anticoagulants. Nephrology (Carlton). 2009 Aug;14(5):462-70. doi:
10.1111/j.1440-1797.2009.01128.x.
3. McMichael M; New models of hemostasis. Top Companion Anim Med. 2012 May;27(2):40-5. doi:
10.1053/j.tcam.2012.07.005. Epub 2012 Aug 29.
4. De Caterina R, Husted S, Wallentin L, et al; Anticoagulants in heart disease: current status and perspectives. Eur Heart J.
2007 Apr;28(7):880-913. Epub 2007 Apr 10.

Page 7 of 7
5. De Caterina R, Husted S, Wallentin L, et al; General mechanisms of coagulation and targets of anticoagulants (Section I).
Position Paper of the ESC Working Group on Thrombosis--Task Force on Anticoagulants in Heart Disease. Thromb
Haemost. 2013 Apr;109(4):569-79. doi: 10.1160/TH12-10-0772. Epub 2013 Feb 28.
6. Heemskerk JW, Mattheij NJ, Cosemans JM; Platelet-based coagulation: different populations, different functions. J Thromb
Haemost. 2013 Jan;11(1):2-16. doi: 10.1111/jth.12045.
7. Bolton-Maggs PH, Pasi KJ; Haemophilias Aand B. Lancet. 2003 May 24;361(9371):1801-9.
8. van Herrewegen F, Meijers JC, Peters M, et al; Clinical practice: the bleeding child. Part II: disorders of secondary
hemostasis and fibrinolysis. Eur J Pediatr. 2012 Feb;171(2):207-14. doi: 10.1007/s00431-011-1571-x. Epub 2011 Sep 17.
9. DeSancho M; Bleeding Disorders, Holland-Frei Cancer Medicine, 6th Edition, 2003.
10. Chalmers EA; Neonatal coagulation problems. Arch Dis Child Fetal Neonatal Ed. 2004 Nov;89(6):F475-8.
11. Blee TH, Cogbill TH, Lambert PJ; Hemorrhage associated with vitamin C deficiency in surgical patients. Surgery. 2002
Apr;131(4):408-12.
12. Leibovitch I, Modjtahedi S, Duckwiler GR, et al; Lessons learned from difficult or unsuccessful cannulations of the superior
ophthalmic vein in the treatment of cavernous sinus dural fistulas. Ophthalmology. 2006 Jul;113(7):1220-6.
13. Turan A, Dalton JE, Turner PL, et al; Preoperative prolonged steroid use is not associated with intraoperative blood
transfusion in noncardiac surgical patients. Anesthesiology. 2010 Aug;113(2):285-91. doi:
10.1097/ALN.0b013e3181e6a195.
14. Schafer AI; Molecular basis of the diagnosis and treatment of polycythemia vera and essential thrombocythemia. Blood.
2006 Jun 1;107(11):4214-22. Epub 2006 Feb 16.
15. Bolton-Maggs PH, Chalmers EA, Collins PW, et al; Areview of inherited platelet disorders with guidelines for their
management on behalf of the UKHCDO. Br J Haematol. 2006 Dec;135(5):603-33.
16. Tosetto A; The Role of Bleeding History and Clinical Markers for the Correct Diagnosis of VWD. Mediterr J Hematol Infect
Dis. 2013 Jul 12;5(1):e2013051. doi: 10.4084/MJHID.2013.051. Print 2013.
17. White B et al; Work-up of a Bleeding Adult: in Textbook of Haemophilia, 2008
18. Webster GF; Common skin disorders in the elderly. Clin Cornerstone. 2001;4(1):39-44.
19. Karnath B; Easy Bruising and Bleeding in the Adult Patient, 2005
20. Federici AB; Clinical diagnosis of von Willebrand disease. Haemophilia. 2004 Oct;10 Suppl 4:169-76.
21. Franchini M; The platelet function analyzer (PFA-100): an update on its clinical use. Clin Lab. 2005;51(7-8):367-72.
22. Naik S, Teruya J, Dietrich JE, et al; Utility of platelet function analyzer as a screening tool for the diagnosis of von
Willebrand disease in adolescents with menorrhagia. Pediatr Blood Cancer. 2013 Jul;60(7):1184-7. doi:
10.1002/pbc.24456. Epub 2013 Jan 17.
23. University of Washington Department of Laboratory Medicine Reference Laboratory Services ; Handbook of Diagnostic
Hemostasis and Thrombosis Tests, 2005.
24. Street AM, Ljung R, Lavery SA; Management of carriers and babies with haemophilia. Haemophilia. 2008 Jul;14 Suppl
3:181-7.

Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical
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For details see our conditions.
Original Author:
Dr Chloe Borton

Current Version:
Dr Laurence Knott

Peer Reviewer:
Dr John Cox

Document ID:
1872 (v22)

Last Checked:
13/01/2014

Next Review:
12/01/2019

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